Melanoma, a malignant neoplasm, is derived from cells that are capable of forming melanin, arising most commonly in the skin of any part of the body and in the eye, or rarely, in the mucus membrane of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or lentigo maligna. In the early phases, the cutaneous form is characterized by a proliferation of cells at the dermal epidermal junction which soon invades adjacent tissues. The cells vary in amount and pigmentation of cytoplasm; the nuclei are relatively large and frequently bizarre in shape, with prominent acidophilic nucleoli; the mitotic figures tend to be numerous. Melanomas frequently metastasize widely; regional lymph nodes, skin, liver, lungs, and brain are likely to be involved.
In January 1985, the Environmental Protection Agency (EPA) predicted that depletion of the Earth's Ozone layer (approximately expected to diminish by 10% because of human activities), which guards against ultraviolet (UV) radiation from space, would cause an increase in the number of skin cancer cases worldwide (an estimated annual increase of two million cases by the year 2050), including melanomas. Also, exposure to higher levels of ultraviolet radiation may also promote cataracts and immune system dysfunction.
Public health efforts have focused on encouraging people to use sunscreen, avoid outdoor activities during peak exposure times, perform frequent self-checks of the skin, and visit dermatologists when irregularities are noted.
UV radiation represents a definitive risk factor for skin cancer, especially when exposure occurs in combination with certain underlying genetic traits, such as red hair and fair skin. Pigmentation of the skin results from the synthesis of melanin in the pigment-producing cells, the melanocytes, followed by distribution and transport of pigment granules to neighboring keratinocytes. It is commonly believed that melanin is crucial for absorption of free radicals that have been generated within the cytoplasm by UV and acts as a direct shield from UV and visible light radiation.
UV-induced pigmentation (sun tanning) requires induction of α-melanocyte-stimulating hormone (α-MSH) secretion by keratinocytes. α-MSH and other bioactive peptides are cleavage products of Pro-Opiomelanocortin (POMC). The p53 tumor suppressor gene is one of the most frequent targets for genetic alterations in cancer. The p53 is a transcriptional regulator of the POMC gene, which translates to proteins that cause the melanocytes to produce melanin, which wards off skin cancer by absorbing UV radiation. Direct mutational inactivation of p53 is observed in close to half of all human tumors. Malignant melanoma is a skin cancer which is, by far, one of the hardest cancers to treat today.
Dacarbazine (DTIC) is the only agent used to treat metastatic malignant melanoma. In addition, Dacarbazine is also indicated for Hodgkin's lymphoma as a secondary line therapy when used in combination with other effective drugs. Chemically, DTIC is 5-(3,3-dimethyl-1-trizeno)-imidazole-4-carboxamide with the following structural formula:
Dacarbazine, however, requires bioactivation in vivo by the liver. One of the methyl groups of the dimethyltriazeno functionality is activated by liver microsomal enzymes and, in particular, by the Cytochrome P450, to oxidation, resulting in a hydroxymethyl group. Thus, the oxidative mono-demethylation of the dimethyltriazeno functionality affords mono-methyltriazene. The monomethyltriazene metabolite, 3-methyl-(triazen-1-yl)-imidazole-4-carboxamide (MTIC) is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active alkylating species. The Cytochrome P450 enzymes play only a minor role in the metabolism of MTIC.
Temozolomide is also a similar imidazotetrazine alkylator that methylates DNA at nucleophilic site. Temozolomide as a bicyclic compound is orally bioavailable, more lipophilic, and spontaneously converted to MTIC, and also seems to generate less nausea. The O6-methylguanine adducts causes a mismatch during DNA replication and the addition of a thymidine, instead of cytosine, to the newly formed DNA strand. Because of the excellent CNS biodistribution, temozolomide has been useful as a radiosensitizer in both primary brain tumors and CNS metastases. Temozolomide improves quality of life when used with radiation in patients with brain metastases. Unlike Dacarbazine, Temozolomide has activity against sarcoma. Thus the analogous bicyclic Temozolomide derivative having Selenium may be useful in sarcoma radiosensitization for primary control as well as for the treatment of metastases. Temozolomide is a radiosensitizer that is well tolerated and has modest side effects. The combination of Temozolomide and Irinotecan is more than additive against some cancers. The author(s) Patel, V. J. et al., Clin. Cancer Res., 2000, 6, 4154-4157 report that their experience confirms a high response rate in relapsed Ewing's sarcoma and DSRCT that is possibly even higher than that reported in the literature. The Temozolomide plus Irinotecan combination is less immune suppressive than standard cyclophosphamide-containing regimens. This might be especially important in Ewing's sarcoma since the author(s) De Angulo, G. et al., J. Pediatr. Hematol. Oncol., 2007, 29, 48-52 have shown that lymphocyte recovery (i.e., absolute lymphocyte count >500 on day 15 after the first cycle of chemotherapy) is associated with significantly higher survival in Ewing's sarcoma. Temozolomide or Dacarbazine has also been combined with other drugs including Gemcitabine and Doxorubicin liposomes. The disappearance of DTIC from the plasma is biphasic with an initial half life of 19 minutes and a terminal half life of five hours. In a patient with renal and hepatic dysfunctions, the half lives were lengthened to 55 minutes and 7.2 hours, respectively. The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in six hours. DTIC is subject to renal tubular secretion rather than Glomerular Filtration. At therapeutic concentrations, DTIC is not appreciably bound to human plasma protein.
In humans, DTIC is extensively degraded. Besides unchanged DTIC, AIC is a major metabolite of DTIC excreted in the urine. Although the exact mechanism of action of DTIC is not known, three hypotheses have been offered:                1. Inhibition of DNA synthesis by acting as a purine analog        2. Acting as an alkylating agent        3. Interaction with sulfhydryl (SH) groupsThus, the biochemical mechanism of action of the resulting MTIC reactive species whose cytotoxicity involved in generation of methyl carbonium ion in vivo is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.        
Alternatively, DTIC, prior to its metabolism to the monomethyltriazene, is oxidized initially to monohydroxymethyl and finally to an aldehyde. The monomethyltriazene, in its aldehyde form prior to oxidative monodemethylation, is cyclized to the cyclic compound (as shown in Scheme 1) which interferes with the double helix DNA structure and blocks replication of the cancer cells.
The imidazole ring system of the Dacarbazine is hydrophilic in nature. Therefore, there is a need in the art for possibly effective binding to the melanin such that the cytotoxic functionality of the molecule is one hundred percent effective. Thus, the present inventors have aimed to provide novel compounds with increased lipophilicity thereby providing more target specificity. Thus, Selenophene, which has a five-membered aromatic heterocyclic ring system, with Selenium in the ring is lipophilic in nature and may have effective binding by increased avidity to the melanin; as a result, one would be able to get the same therapeutic effectiveness at a significantly lower dose, hence minimizing the toxicity. This would in turn afford high specificity with a larger window of the Therapeutic Index (TI). In general, for the treatment of cancer patients, a larger therapeutic index is preferred. This is because; one would like to start the therapeutic regimen with a very high Maximum Tolerated Dose (MTD) such that the cancer cells would be hit hard in the first chemotherapy itself. Otherwise, the surviving cancer cells would repair the DNA damage and subsequently metastasize to the other organs. In addition, the cancer cells that survived from the first treatment would become resistant to the second chemotherapy again, if needed. And besides, due to weakness of the immune system from the first chemotherapy, a suboptimal dose would be given in the second treatment that would contribute to toxicity.
As shown in Scheme-1, unlike DTIC, better interaction of the selenophene ring system with the SH groups on the surface of the tumor antigen results in increased efficacy. This is because of selenium (Se) being larger atom and hence a five membered heterocyclic aromatic selenophene ring system resemble a phenyl ring in space, would contribute it's loan pair of electrons to the rest of the ring for better interaction with sulfhydryls at the tumor site. In addition, due to its electronic configuration, the heterocyclic aromatic selenophene ring system may be superior over DTIC by way of inhibition of DNA synthesis by acting as a purine analog as well as acting as an alkylating agent. Also, unlike DTIC, while Amino Imidazole Carboxamide (AIC) is inactive by itself, the corresponding Amino Selenophene Carboxamide (ASC) would very well be active in vivo via de-localization of electrons from the ring selenium for increased efficacy. Both AIC and ASC are incorporate into DNA. Thus, the novel triazeno selenophene analogs have several additional advantages inherently built in within the structure over Dacarbazine for increased activity.
Therefore, in order for the dose regimen to be effective, possibly high melanin binding moieties such as selenophene system could offer a therapeutic treatment having all the three biochemical mechanisms of action superior to DTIC (Dacarbazine) with a possible positive outcome leading to complete responses. Thus, the present invention aims to fulfill this unmet medical need of selectively binding to the targeted melanoma cells and sparing the normal cells thereby increasing the target to non-target cell ratio and further providing other related advantages as described herein.
Angiogenesis, or neovascularization, is the process of generating new blood vessels derived as extensions from the existing vasculature. Angiogenesis plays an important role in the growth and spread of cancer. New blood vessels “feed” the cancer cells with oxygen and nutrients, allowing these cells to grow, invade nearby tissue, spread to other parts of the body, and form new colonies of cancer cells. Therefore, anti-angiogenesis or inhibition of angiogenesis has been considered as a potential therapeutic strategy for controlling tumor growth and metastatic spread of cancer cells.
The inventors of the present invention during their ongoing effort to invent novel compound(s), have surprisingly found that Selenopheno triazene compounds of general formulae (I) and (II) were potent antimelanoma agents, angiogenesis inhibitors and are effective for the prevention, control and treatment of melanoma, cancers and other vascular diseases.